CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling
Katrin Faber, … , Claudia Scholl, Stefan Fröhling
Katrin Faber, … , Claudia Scholl, Stefan Fröhling
Published December 3, 2012
Citation Information: J Clin Invest. 2013;123(1):299-314. https://doi.org/10.1172/JCI64745.
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Research Article Oncology

CDX2-driven leukemogenesis involves KLF4 repression and deregulated PPARγ signaling

Abstract

Aberrant expression of the homeodomain transcription factor CDX2 occurs in most cases of acute myeloid leukemia (AML) and promotes leukemogenesis, making CDX2, in principle, an attractive therapeutic target. Conversely, CDX2 acts as a tumor suppressor in colonic epithelium. The effectors mediating the leukemogenic activity of CDX2 and the mechanism underlying its context-dependent properties are poorly characterized, and strategies for interfering with CDX2 function in AML remain elusive. We report data implicating repression of the transcription factor KLF4 as important for the oncogenic activity of CDX2, and demonstrate that CDX2 differentially regulates KLF4 in AML versus colon cancer cells through a mechanism that involves tissue-specific patterns of promoter binding and epigenetic modifications. Furthermore, we identified deregulation of the PPARγ signaling pathway as a feature of CDX2-associated AML and observed that PPARγ agonists derepressed KLF4 and were preferentially toxic to CDX2+ leukemic cells. These data delineate transcriptional programs associated with CDX2 expression in hematopoietic cells, provide insight into the antagonistic duality of CDX2 function in AML versus colon cancer, and suggest reactivation of KLF4 expression, through modulation of PPARγ signaling, as a therapeutic modality in a large proportion of AML patients.

Authors

Katrin Faber, Lars Bullinger, Christine Ragu, Angela Garding, Daniel Mertens, Christina Miller, Daniela Martin, Daniel Walcher, Konstanze Döhner, Hartmut Döhner, Rainer Claus, Christoph Plass, Stephen M. Sykes, Steven W. Lane, Claudia Scholl, Stefan Fröhling

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Figure 8

Relationship between CDX2 and KLF4 expression and analysis of the KLF4 regulatory region in human CRC cells.

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Relationship between CDX2 and KLF4 expression and analysis of the KLF4 r...
(A) CDX2 mRNA expression of CRC cell lines. (B) Decreased KLF4 mRNA levels in response to CDX2 knockdown in human CRC cell lines. (C) Increased KLF4 mRNA levels in response to ectopic CDX2 expression in HT-29 cells. (D) ChIP showing occupancy of sites 1, 2 and (to a lesser extent) 5 in the KLF4 regulatory region by HA-CDX2 in HT-29 cells. The location of possible CDX2 binding sites is shown in Figure 2D. GAPDH served as control locus. (E) ChIP showing increased H3K4me3 enrichment and unchanged H3K27me3 occupancy in HT-29 cells upon expression of HA-CDX2. The location of the H3K4me3 and H3K27me3 marks is shown in Figure 2D. AFP and GAPDH served as negative and positive control loci for H3K4me3; GAPDH and SAT2 served as negative and positive control loci for H3K27me3. (F) Quantitative DNA methylation levels at the KLF4 locus in HT-29 cells and K-562 myeloid leukemia cells. The KLF4 TSS (+1) and CDX2 binding sites 3 and 4 are marked, and their relative positions are given. The green bar depicts a CpG island (CGI). The dashed line indicates a region where DNA methylation could not be assessed.